Abstract:The computational approach applicable for the molecular dynamics (MD)-based techniques is proposed to predict the ligand-protein binding affinities dependent on the ligand stereochemistry. All possible stereoconfigurations are expressed in terms of one set of force-field parameters [stereoconfiguration-independent potential (SIP)], which allows for calculating all relative free energies by only single simulation. SIP can be used for studying diverse, stereoconfiguration-dependent phenomena by means of various … Show more
“…Differences between the global minimum (corresponding to the ligand located in the binding cavity) and the “plateau” region (corresponding to the ligand in the bulk solution, outside the receptor) for considered FEPs both were larger than those expected on the basis of experimental data (Jozwiak et al 2010 ; Toll et al 2012 ). Recent results (Plazinska et al 2014 ) obtained for the fenoterol–β 2 -AR system which were in a good agreement with available thermodynamic data confirm that inaccuracies inherent in the force field and the initial location of the ligand were rather small. We therefore speculated that repulsive interactions between the N-terminus region and the ligand molecule (both bear a positive charge) cause the increase of the free energy.…”
Section: Resultssupporting
confidence: 77%
“…[ 3 H]-CGP-12177 and [ 3 H]( R , R )-methoxyfenoterol) revealed significant differences between the thermodynamic characteristics of binding of the fenoterol stereoisomers to different conformations of β 2 -AR (Toll et al 2012 ). Subsequent molecular simulations confirmed experimentally determined thermodynamic data for binding (∆G 0 , ∆H 0 , ∆S 0 ) and showed that structurally similar compounds (stereoisomers of fenoterol), the full agonists of β 2 -AR, bind to the inactive and active conformational states of β 2 -AR with different affinities and thermodynamic data (Jozwiak et al 2010 ; Toll et al 2012 ; Plazinska et al 2014 ). Fig.…”
Section: Introductionmentioning
confidence: 70%
“…1 a) interacts with serines located on TM V: S203 5.42 , S204 5.43 , S20 5.46 (superscript numbers correspond to the general numbering scheme of Ballesteros and Weinstein ( 1995 )), which are involved in binding the agonist (Ring et al 2013 ), inverse agonist (Cherezov et al 2007 ), and antagonist (Wacker et al 2010 ). The protonated amine group of the ligand creates the ionic bridge with the carboxyl group of D113 3.32 (TM III) (Kolinski et al 2012 ; Plazinska et al 2013 , 2014 ), by analogy with such endogenous agonist molecules as adrenaline (Ring et al 2013 ). However, docking and MD simulations revealed different binding of fenoterol to the active and inactive states which result from the receptor crystal structures, especially from different distances between TM V, TM VI, and TM VII.…”
The β2-adrenergic receptor (β2-AR), a G protein-coupled receptor (GPCR), is a physiologically important transmembrane protein that is a target for drugs used for treatment of asthma and cardiovascular diseases. Study of the first steps of ligand recognition and the molecular basis of ligand binding to the orthosteric site is essential for understanding the pharmacological properties of the receptor. In this work we investigated the characteristic features of the agonist association–dissociation process to and from the different conformational forms of β2-AR by use of advanced molecular modeling techniques. The investigation was focused on estimating the free energy profiles (FEPs) corresponding to the process of a full agonist ((R,R)-fenoterol) and an inverse agonist (carazolol) binding and unbinding to and from β2-AR. The two different conformational forms of β2-AR, i.e. active β2-AR–PDB: 3P0G and inactive β2-AR–PDB: 2RH1 were included in this stage of the study. We revealed several significant qualitative differences between FEPs characteristic of both conformational forms. Both FEPs suggest the existence of three transient binding sites in the extracellular domain of β2-AR. Comparison of the residues surrounding these transient binding sites in both β2-AR states revealed the importance of the aromatic residues F194, H932.64, H2966.58, and H178 (extracellular part of β2-AR) in the early stages of the binding process. In addition, slightly different exit and entry paths are preferred by the ligand molecule in the extracellular part of β2-AR, depending on the conformation of the receptor.Electronic supplementary materialThe online version of this article (doi:10.1007/s00249-015-1010-4) contains supplementary material, which is available to authorized users.
“…Differences between the global minimum (corresponding to the ligand located in the binding cavity) and the “plateau” region (corresponding to the ligand in the bulk solution, outside the receptor) for considered FEPs both were larger than those expected on the basis of experimental data (Jozwiak et al 2010 ; Toll et al 2012 ). Recent results (Plazinska et al 2014 ) obtained for the fenoterol–β 2 -AR system which were in a good agreement with available thermodynamic data confirm that inaccuracies inherent in the force field and the initial location of the ligand were rather small. We therefore speculated that repulsive interactions between the N-terminus region and the ligand molecule (both bear a positive charge) cause the increase of the free energy.…”
Section: Resultssupporting
confidence: 77%
“…[ 3 H]-CGP-12177 and [ 3 H]( R , R )-methoxyfenoterol) revealed significant differences between the thermodynamic characteristics of binding of the fenoterol stereoisomers to different conformations of β 2 -AR (Toll et al 2012 ). Subsequent molecular simulations confirmed experimentally determined thermodynamic data for binding (∆G 0 , ∆H 0 , ∆S 0 ) and showed that structurally similar compounds (stereoisomers of fenoterol), the full agonists of β 2 -AR, bind to the inactive and active conformational states of β 2 -AR with different affinities and thermodynamic data (Jozwiak et al 2010 ; Toll et al 2012 ; Plazinska et al 2014 ). Fig.…”
Section: Introductionmentioning
confidence: 70%
“…1 a) interacts with serines located on TM V: S203 5.42 , S204 5.43 , S20 5.46 (superscript numbers correspond to the general numbering scheme of Ballesteros and Weinstein ( 1995 )), which are involved in binding the agonist (Ring et al 2013 ), inverse agonist (Cherezov et al 2007 ), and antagonist (Wacker et al 2010 ). The protonated amine group of the ligand creates the ionic bridge with the carboxyl group of D113 3.32 (TM III) (Kolinski et al 2012 ; Plazinska et al 2013 , 2014 ), by analogy with such endogenous agonist molecules as adrenaline (Ring et al 2013 ). However, docking and MD simulations revealed different binding of fenoterol to the active and inactive states which result from the receptor crystal structures, especially from different distances between TM V, TM VI, and TM VII.…”
The β2-adrenergic receptor (β2-AR), a G protein-coupled receptor (GPCR), is a physiologically important transmembrane protein that is a target for drugs used for treatment of asthma and cardiovascular diseases. Study of the first steps of ligand recognition and the molecular basis of ligand binding to the orthosteric site is essential for understanding the pharmacological properties of the receptor. In this work we investigated the characteristic features of the agonist association–dissociation process to and from the different conformational forms of β2-AR by use of advanced molecular modeling techniques. The investigation was focused on estimating the free energy profiles (FEPs) corresponding to the process of a full agonist ((R,R)-fenoterol) and an inverse agonist (carazolol) binding and unbinding to and from β2-AR. The two different conformational forms of β2-AR, i.e. active β2-AR–PDB: 3P0G and inactive β2-AR–PDB: 2RH1 were included in this stage of the study. We revealed several significant qualitative differences between FEPs characteristic of both conformational forms. Both FEPs suggest the existence of three transient binding sites in the extracellular domain of β2-AR. Comparison of the residues surrounding these transient binding sites in both β2-AR states revealed the importance of the aromatic residues F194, H932.64, H2966.58, and H178 (extracellular part of β2-AR) in the early stages of the binding process. In addition, slightly different exit and entry paths are preferred by the ligand molecule in the extracellular part of β2-AR, depending on the conformation of the receptor.Electronic supplementary materialThe online version of this article (doi:10.1007/s00249-015-1010-4) contains supplementary material, which is available to authorized users.
“…The acceptance ratio is only related to the parameters in the temperature space, and it dependent on the extensive quantities implicitly, that is the potential energy E . Therefore, when the system size increases, the exchange rate will not decrease in PCST, this is different from parallel tempering, which usually employs more than 20 copies . In practice, only 2–3 copies are enough to maintain a high rate of exchange between neighboring copies.…”
This paper reports a method for high-accuracy protein structural refinement, which is a direct extension of the method in our recent publication (Zang, J Chem Phys 2018; 149:072319). It combines a parallel continuous simulated tempering (PCST) method with a temperature-dependent restraint and a blind model selection scheme. In this work, a single-reference-based restraint in previous work was changed to an ensemble-based model (EBM), in which the non-bonded Lennard-Jones term for each contacting atomic pair in previous restraining potential was replaced by a multi-Gaussian function whose parameters are derived from an ensemble of structures such as the ones from various CASP participating groups. The purpose of EBM is to take advantage of partial "correctness" distributed among members of the structural ensemble. Totally 18 targets were refined from the refinement category of CASP10, CASP11 and CASP12. In Top-1 group, 11 out of 18 targets had better models (greater GDT_TS scores) than the CASPR participants. In Top-5 group, nine out of 18 were better. Our results show that PCST-EBM method can considerably improve the low-accuracy structures.
“…. An important feature of this protocol is that the acceptance ratio is only related to the parameters in the temperature space, whereas it does not have an explicit dependence on the extensive quantities, i.e., the potential energy E. Therefore, compared with parallel tempering, which usually employs more than 20 copies, [39][40][41][42][43][44] this method does not suffer from a decrease of exchange rate with the increase of the system size. In practice, only 2-3 copies are employed, yet it is still capable of maintaining a high rate of exchange between neighboring copies.…”
Section: A Temperature-based Enhanced Samplingmentioning
In this paper, we report results of using enhanced sampling and blind selection techniques for high-accuracy protein structural refinement. By combining a parallel continuous simulated tempering (PCST) method, previously developed by Zang [J. Chem. Phys., 044113 (2014)], and the structure based model (SBM) as restraints, we refined 23 targets (18 from the refinement category of the CASP10 and 5 from that of CASP12). We also designed a novel model selection method to blindly select high-quality models from very long simulation trajectories. The combined use of PCST-SBM with the blind selection method yielded final models that are better than initial models. For Top-1 group, 7 out of 23 targets had better models (greater global distance test total scores) than the critical assessment of structure prediction participants. For Top-5 group, 10 out of 23 were better. Our results justify the crucial position of enhanced sampling in protein structure prediction and refinement and demonstrate that a considerable improvement of low-accuracy structures is achievable with current force fields.
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